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Background: Tularemia, caused by a Gram-negative bacterium Francisella tularensis, is an occasional disease of cats in the midwestern United States and a public health concern due to its zoonotic potential. Different environmental, climatic, and pet-owner's housing and socioeconomic conditions were evaluated as potential risk factors for feline tularemia using Geographic Information Systems (GIS) in a retrospective case-control study. Methods: The study included 46 cases identified as positive for tularemia based upon positive immunohistochemistry, isolation of F. tularensis using bacterial culture, and 4-fold or greater change in serum antibody titer for F. tularensis. Cats with a history of fever, malaise, icterus, and anorexia but no lesions characteristic of tularemia and/or negative immunohistochemistry, no isolation of bacteria in bacterial culture, and less than 4-fold raise in serum antibody titer for F. tularensis were treated as controls (n = 93). Candidate geospatial variables from multiple thematic sources were analyzed for association with case status. Variables from National Land Cover Dataset, Soil Survey Geographic Database, US Census Bureau, and Daymet were extracted surrounding geocoded case-control household locations. Univariable screening of candidate variables followed by stepwise multivariable logistic modeling and odds ratios were used to identify strengths of variable associations and risk factors. Results: Living in a residence located in newly urbanized/suburban areas, residences surrounded by areas dominated by grassland vegetation, and mean vapor pressure conditions recorded during the 8th week prior to case arrival at the hospital are significant risk factors for feline tularemia. Conclusions: Prevention strategies such as acaricide applications in residential backyards during spring and early summer periods and any behavior modifications suitable for cats that will prevent them from contracting infection from ticks or dead animals are necessary. Mean vapor pressure conditions recorded during the 8th week prior to case arrival at a diagnostic facility is a predictor for feline tularemia. [ABSTRACT FROM AUTHOR]